Pregnanolones and a method of producing the same



Patented Mar. 21, 1939 UNITED STATES PATENT OFFICE PREGNANOLONES AND AMETHOD OF PRO- DUCING THE SAME.

Friedrich Hiidebrandt,

Hohen Neuendorf, near Berlin, Germany, assignor to ScheringAktiengesellschaft, a corporation of Germany 11 Claims.

This invention relates to pregnanolones and a method of producing thesame.

The present application is a continuation-inpart of my copendingapplication Serial No.

a 36,984, filed August 20, 1935.

Pregnanolones have already been produced from pregnandiones by treatingpregnandiones with nascent hydrogen or with hydrogen in the presence ofcatalysts. Thereby, however, it may very readily happen that instead ofmerely reducing a single keto group both keto groups of thepregnandiones are reduced to secondary alcohol groups, so that oncarrying out the reaction pregnandiols are obtained instead of thedesired pregnanolones.

In accordance with the present invention it is possible to overcomethese disadvantages to a considerable extent and to producepregnanolones in a simple manner from pregnandiones. The process of theinvention consists in treating pregnandiones with such organo-metalliccompounds as tend toward the formation of unsaturated hydrocarbons,decomposing the reaction product in a manner known per se, for example,by treating the same with water and dilute acid, and isolating thepregnanolones formed.

As organo-metallic compounds which tend toward the formation ofunsaturated hydrocarbons there are suitable for the present purposecompounds like propyl-, isopropyl, isobutyl-, cyclohexyland the likemagnesium halogenides and others, as they are mentioned, for example, inHouben-Weyl, Methoden der organischen Chemie, third edition, secondvolume, page 248 and third volume page 82. The product of the process isintended to serve as intermediate product for the production oftherapeutically valuable substances.

The following examples illustrate the invention 40 without, however,limiting the same to them:

Example 1 3.163 grams of pregnandione with a melting point of 116-121 C.are dissolved in 250 cos. of dry ether and the solution is treated inthe course of one hour with an ethereal solution of isopropyl magnesiumiodide produced from 0.973 g. of magnesium turnings, 3.992 cos. ofisopropyl iodide in 40 cos. of dry ether and a trace of iodine.Thereupon the ether is completely evaporated and the residue is heatedin an oil bath for 1 hour to 120 C. After cooling, the white preparationis decomposed, that is, hydrolyzed with water and dilute hydrochloricacid, extracted with ether and the ethereal solution is washedconsecutively with water, sodium thiosulphate solution and again withwater, dried and evaporated. As residue there remains a light yellowvery viscous resin.

The reaction product can be freed from any non-alcoholic constituentsstill present by condensation with m-benzoic acid sulphochloride andprecipitation with ether of the pyridoniumsalt of the ester acid formedthereby. After splitting off the ester salt by heating for 3 hours with5% aqueous methanolic (1:1) caustic potash lye, there is obtained aviscous slightly coloured resin which boils at about -125" C. in a highvacuum under a pressure of about 3-5/1000 mm. As the product stillcontains a keto group, it can be isolated from accompanying non-ketonicsubstances with the aid of ketone reagents, that is, substances having afree amino group and capable of condensing with compounds having ketogroups. Thus onheating with an excess of semicarbazide acetate inmethanolic solution a crude semicarbazone having the formula C22H37O2N3is formed that is very diflicultly soluble in ether and has a meltingpoint of 143-155 C. (with decomposition) Example 2 1 gram ofpregnandione of M. P. 113-121 C. is dissolved in 50 cos. of dry etherwhereupon the solution is treated with an ethereal solution of isobutylmagnesium iodide produced from 0.308 gram of dry magnesium turnings,2.329 grams oi freshly distilled isobutyl iodide in 40 cos. of dry etherand a trace of iodine. The reaction liquid is then further heated toboiling for about 1 hour while stirring. After evaporation of the otherthe remaining residue is decomposed with ice and dilute hydrochloricacid (1:5), extracted with ether and the ethereal solution washedconsecutively with water, sodium thiosulphate solution and again withwater, dried and evaporated to dryness. As residue there remains a purewhite amorphous mass. By repeated recrystallization of the crudeproduct, for example, from methanol, a well defined crystalline productof M. P. 204-216" C. corresponding to the general formula CziHsiOz, canbe isolated.

Of course, various other modifications and changes in the reactionconditions and the like may be made by those skilled in the art inaccordance with the principles set forth herein and in the claimsannexed hereto.

What I claim is:

1. Process for the production of a pregnanolone, comprising treating apregnandione with an organo-magnesium halide that tends toward theformation of an unsaturated hydrocarbon hydrolyzing the reactionproduct, and reacting the pregnanolone formed with semicarbazideacetate, separating the semicarbazone, and hydrolyzing the same.

2. Process for the production of a pregnanolone, comprising treating apregnandione with an organo magnesium halide that tends to toward theformation of an unsaturated hydrocarbon, hydrolyzing the reactionproduct, and isolating the pregnanolone formed.

3. Process for the production of a prognanolone, comprising treating apregnandione with isopropyl magnesium iodide, hydrolyzing the reactionproduct, and isolating the pregnanolone formed.

4. Process for the production of a pregnanolone, comprising treating apregnandione with isobutyl magnesium iodide, hydrolyzing the reactionproduct, and isolating the pregnanolone formed.

5. A pregnanolone having a melting point of 204-216 C. and produced frompregnandiones by treating the same with an organo-magnesium halide thattend toward the formation of unsaturated hydrocarbons, hydrolyzing thereaction product, and isolating the pregnanolone formed.

6. A pregnanolone of the general formula 021113402, having a meltingpoint of 204-216 C.

'7. A pregnanolone semicarbazone of the general formula C22H3'1O2N3,having a melting point of 143-155 C.

8. Process for the production of a pregnanclone compound, comprisingtreating a pregnandione with an organo-magnesium halide that tendstoward the formation of an unsaturated hydrocarbon, hydrolyzing thereaction product, and reacting the pregnanolone so formed with asemi-carbazide.

9. A pregnanolone compound of the group consisting of pregnanolonehaving the general formula C21H34O2 and melting at 204-216 C. and thereaction products thereof with semicarbazides.

10. The method according to claim 2 wherein the isolation of thepregnanolone is efifected by treating the reaction mixture with areagent having a free amino group and capable of forming a condensationproduct with the carbonyl group of the pregnanolone, separating andhydrolyzing the reaction product so formed and recovering the purifiedpregnanolone.

11. Process for the production of a pregnanolone, comprising treating apregnandione with a lower alkyl magnesium iodide, hydrolyzing thereaction product, and isolating the pregnanolone formed.

FRIEDRICH HILDEBRANDT.

